Use of 5HT3-receptor-antagonists

ABSTRACT

A method of treatment for Chronic Fatigue Syndrome (CFS) comprising reducing the effect of serotonin by administering a dosage unit comprised of 5HT 3 -receptor-antagonist in an amount effective to decrease the effect of serotonin.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation of U.S. patent applicationSer. No. 09/868,972, filed Sep. 4, 2001.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to a new use for5HT₃-receptor-antagonists. CFS, chronic fatigue syndrome, was defined asa diagnostic entity at the end of the eighties and has been the subjectof numerous studies and publications. Particularly problematic withrespect to the diagnosis of CFS is the fact that a complex of symptomsof pathological fatigue and susceptibility to fatigue is present,wherein the present symptoms are at least partially also to beencountered in a number of other internistic and psychiatric illnesses.

[0003] Thus, one must note the absence of symptoms, other than thosewhich can be attributed to other illnesses, useful when diagnosing CFS.

[0004] Principally there is the question of what fatigue actually is.Generally, it is referred to as a physiological lack of capability, butmay also be felt as lack of drive, lack of stamina and physicalweakness. Mental fatigue can be divided into a bad ability toconcentrate and remember, lack of interest in activities and sleepinessthroughout the day.

[0005] On the other hand, fatigue is a natural phenomenon occurringafter physical or psychological stress which goes away after resting orsleeping. Thus, the differentiation between “normal” and “abnormal”fatigue is of importance. It is helpful to note that patients sufferingfrom CFS usually also suffer from further symptoms which can be employedfor diagnosis.

[0006] Since comparatively short term conditions of fatigue may occurduring or after an illness or under strong and lasting stress, oneconcludes the presence of CFS as chronic illness only on the occasion ofsymptoms persisting for at least six months.

[0007] Generally, the presence of CFS is determined in a patient in whomthe fatigue is medically not explainable even after careful clinicalinvestigation. It is generally acknowledged that patients with a definedorganic illness are to be excluded from the group of CFS patients. Withrespect to psychological illnesses, there is less agreement in relationto a corresponding exclusion. Some scientists are of the opinion thatpatients suffering from depression and anxiety should be excluded sincean appropriate explanation for the fatigue in these patients is present.Other scientists are of a different opinion.

[0008] In the presence of CFS, symptoms of chronic mental and physicalfatigue usually occur which grow worse with activity and are oftenaccompanied by pain in the muscles. In this respect, patients frequentlyreport that they are fit and capable for a short period of time, butthen suffer from heavy fatigue for hours or days. Further symptoms thatordinarily are reported include non-relaxing sleep, dizziness andbreathlessness as well as head aches and further symptoms. Depressiveperiods and conditions of anxiety also occur in part of the patients.The diagnosis of CFS is therefore always a diagnosis by means ofexclusion.

[0009] Until now no effective way of treatment could be found fortreating CFS. Frequently antidepressants are employed for therapy, but afirst comprehensive, randomized placebo-controlled investigation onantidepressants was negative in result (Vercoulen, Jan H. M. M. et al.,Lancet 1996, 347:858-61). The subject of the referenced investigationwas fluoxetin, wherein in the end not even patients with accompanyingsymptoms of depression showed a positive result in response to a dailydose of 20 mg fluoxetin. This already points out a specific pathogenesisof CFS in contrast to depressive illnesses.

[0010] Since fluoxetin is a selective serotonin reuptake inhibitor, thereferenced investigation concludes that an influence of disorders inserotonin metabolism on the occurrence of depression like symptoms indepressive CFS-patients is unlikely. In this connection reference ismade to an investigation relating to serotonin processes in associatonwith CFS (Yatham L. N. et al., Can. J. Psychiatry 1995, 40, 93-96).

[0011] Studies indicate there are concrete indications for serotonicactivity in the brain, such as is shown by the significantly increasedrise of prolactin in the serum after an acute application ofD-Feufluoroamin on patients with CFS.

[0012] It is generally to be noticed that indications of a convenientand effective therapy for the treatment of CFS are lacking.

SUMMARY OF THE INVENTION

[0013] It is object of the present invention to provide compounds thatare suitable for the manufacture of drugs for the treatment of CFS.

[0014] The present object is achieved by the features of claim 1.Advantageous embodiments of the invention form the subject matter of thedepending claims.

DETAILED DESCRIPTION

[0015] The present invention is based on the finding that the use ofantidepressants with CFS which amplify the action of serotonin is notappropriate, which is also evidenced by the cited study with respect tofluoxetin. First, this is a turn away from therapeutic methods that werecustomary until now and which essentially were focussed on the presenceof depressive conditions. Thus, the use of substances is suggested whichreduces the effect of serotonin and which are canalized by the subgroupof the so called 5HT₃-receptors. According to the invention, thepharmacologically known class of the highly specific5HT3-receptor-antagonists, which for example find application in thetreatment of the emesis in the chemotherapy of cancer, are suited forthis purpose.

[0016] In an advantageous embodiment of the present invention Alosetron,Tropisetron, Ondansetron, Granisetron, Bemesetron or combinations of atleast two of the foregoing, very selective acting substances areemployed as 5HT₃-receptor-antagonists. In this respect it is preferredthat the amount of active substance in one dosage unit amounts to 2 to10 mg, an amount of 5 to 8 mg active substance in one dosage unit beingespecially preferred. A daily dosage comprises generally an amount ofactive substance of 2 to 20 mg, particularly preferred is an amount ofactive substance of 5 to 16 mg. If necessary those skilled in the artalso know how to vary the active substance in a dosage unit or the levelof the daily dosage according to the requirements. The factorsdetermining this, such as body weight, overall constitution, response tothe treatment and the like will constantly be monitored by the artisanin order to be able to react accordingly and adjust the amount of activesubstance in a dosage unit or to adjust the daily dosage if necessary.

[0017] Preferably, the substances that are used for producing the drugaccording to the invention, 5HT₃-receptor-antagonists, are processed toan oral or intravenous form of administration to provide possibilitiesfor variation in the application and for providing a possibly mostgentle administration for the respective patient.

[0018] In the following, the present invention is further illustrated bythe way of examples. These examples serve to illustrate and by no meansto restrict the scope of the present invention.

[0019] To revise the effectiveness of the inventive therapeutic approachtwo groups of patients of ten patients were treated with Tropisetron andOndansetron, respectively.

[0020] In the preceding diagnostic the Chronic Fatigue Syndrom (CFS) wasconfined by criteria of classification based on those of the Center ofDisease Control and Prevention, in the edition revised 1994 (Fukuda K.et al., Ann Intern Med. 1994; 121:953-1959). In the judgement, it wasset off from a clinically proven etiologically unclear, persisting orrelapsing fatigue (duration >6 months) that has commenced newly ortimely delimited (not already existing for life), which is not theconsequence of a still lasting overload that does not improve with restand which leads two a considerable reduction of the earlier level ofactivity in education and profession as well as in social and personalareas. Prerequisite is that the occurrence of four or more of thefollowing symptoms which, all have had to exist persisting or relapsingfor at least six consecutive months of illness and which may not havepreceded the fatigue. These symptoms are:

[0021] restriction of the short term memory or concentration severeenough to cause a substantial reduction of the earlier level of activity

[0022] a sore throat (Pharyngitis without pus)

[0023] axillary and lymph nodes of the neck reacting with pain onpressure

[0024] muscle pain

[0025] arthalgia

[0026] headaches of a new quality

[0027] no relaxation by sleep

[0028] worsening of condition for more than 24 hours after efforts.

[0029] By such diagnosis of exclusion according to the foregoingcriteria a group of patients may be confined the prevalence of which islying at about 3% and whose discomforts may not be named differently.The group of patients treated with Tropisetron received the activesubstance in the form of a capsule with an amount of active substance of5 mg/dosage unit, wherein the daily dosage was also 5 mg. The secondgroup of patients received the active substance Ondansetron in form oftablets, wherein a dosage unit contained 8 mg active substance and thedaily dosage consisted of twice a dosage unit, i.e. 16 mg daily.

[0030] The administration of the 5HT₃-receptor-antagonists took placefor over 15 days, respectively. During the study patients were monitoredfor the parameters listed as follows:

[0031] MARDS; days 0 and 15

[0032] VAS (Visual Analog Scale) susceptibility to fatigue/fatigue; days0, 8 and 15

[0033] VAS fitness; days 0, 8 and 15

[0034] daily recording of both of the VAS by the patient himself

[0035] accompanying symptoms; days 0, 8 and 15

[0036] fitness during the test; day 15

[0037] final evaluation by physician and patient; day 15

[0038] The essential changes under therapy were recorded by visualanalog scales that documented the extent of the abnormal susceptibilityto fatigue/fatigue as well as the reduction of fitness. In this respectthe subjectively felt condition for susceptibility to fatigue/fatigue orfitness were marked on a scale comprising a range from 0 to 100, wherein0 means normal susceptibility to fatigue/fatigue or fitness and 100 forthe heaviest susceptibility to fatigue/fatigue or for a 100% reductionin fitness.

[0039] With respect to two visual analog scales a significantimprovement in an amount of more than 35% could be determined in onethird of the patients. This related to both of the groups of thepatients similarly. Additionally, considering the patients reporting ofa pronounced improvement the response rate amounts to about 66%.

[0040] The conducted studies show unambiguously that a pronouncedimprovement in about a third of the patients occurred with regard to themain symptoms of CFS, fatigue and reduction of fitness, a further thirdfeeling at least a minor improvement with respect to the discomforts.Clinically this is a very significant success in therapy, particularlyon the background that other therapeutic approaches have proven to bepractically without effect.

[0041] Another important indication for the therapy of CFS with respectto the effect of the suggested therapy is the fact that in the studiesdescribed herein before a significant improvement of the condition ofthe patients could be noted within the duration of the study of 15 dayswhich is very surprising in view of the persistence of the determinedsymptoms, since the diagnostic symptoms had to be present for more than6 months according to the definition.

[0042] The effect of the substances employed in the study, Tropisetronand Ondansetron, on the inhibition of the 5HT₃-receptor as the commonhighly specific principle of action is based on the only common featureof the presence of a structural element in form of a indol cycle, sincethese two compounds differ considerably in their chemical structure.

1. A method of treatment for Chronic Fatigue Syndrome (CFS) comprisingreducing the effect of serotonin by administering a dosage unitcomprised of 5HT₃-receptor-antagonist in an amount effective to decreasethe effect of serotonin.
 2. The method of claim 1, wherein the5HT₃-receptor-antagonists is selected from the group consisting ofAlosetron, Tropisetron, Ondansetron, Granisetron, Bemesetron, andmixtures thereof.
 3. The method of claim 1, wherein said administeringstep comprises administering said 5HT₃-receptor-antagonist in an amountof 2 to 10 mg.
 4. The method of claim 1, wherein said administering stepcomprises administering a daily dosage of said 5HT₃-receptor antagonistin an amount from 2 to 20 mg.
 5. The method of claim 1, wherein said5HT₃-receptor-antagonist is administered orally.
 6. The method of claim1, wherein said administering said dosage unit comprises administeringsaid dosage unit comprising Tropisetron.
 7. The method of claim 6,wherein said administering said dosage unit comprises administering saiddosage unit comprising Tropisetron and at least one substance selectedfrom the group consisting of Alosetron, Ondansetron, Granisetron,Bemesetron and combinations thereof.
 8. The method of claim 1, whereinsaid 5HT₃-receptor-antagonist is administered intravenously.
 9. Themethod of claim 3, wherein said amount of said 5HT₃-receptor-antagonistcontained in said dosage unit is 5 to 8 mg.
 10. The method of claim 4,wherein said daily dosage of said 5HT₃-receptor-antagonist comprises anamount of said 5HT₃-receptor-antagonist from 5 to 16 mg.